This proposal outlines a five-year plan for the training of the applicant for an academic career studying hepatitis C virus (HCV) pathogenesis. The candidate received a Ph.D. in the laboratory of Dr. Vincent Racaniello, completed a residency training in Internal Medicine and a Clinical Fellowship in Infectious Diseases and is now working in the laboratory of Dr. Paul Bates, her sponsor. Dr. Colston`s research interests currently center on hepatitis C virus entry. She has a background in non-enveloped virus entry and seeks to gain the experience in enveloped viruses needed to attack questions of HCV entry independently. For this purpose, an integrated research and training program is outlined in the Division of Infectious Diseases and the Department of Microbiology. In addition to Dr. Bates, who works on retroviral receptors and viral entry, an advisory board will mentor the candidate`s career development. HCV is the major cause of nonA nonB hepatitis worldwide. There is currently no vaccine to protect against infection and available therapies often do not work well. HCV was cloned and sequenced over 10 years ago but there are many unanswered questions regarding viral pathogenesis. Limitations to the study of HCV are the lack of either a cell culture system or a small animal model. The proposed work is to incorporate HCV glycoproteins into retroviral particles and use these pseudotypes as a model system to study early events in viral infection. Specifically, these pseudotypes will be useful for analyzing HCV glycoprotein function, studying the mechanism of HCV entry, examining the immune response to viral glycoporteins and identifying a cellular receptor(s) for HCV. These studies aim to provide new insights into HCV infection.